title: Macrophage migratory inhibitory factor promotes bladder cancer progression via increasing proliferation and angiogenesis.
abstract: Macrophage migratory inhibitory factor (MIF) is a proinflammatory cytokine shown to promote tumorigenesis. Using the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) model of bladder cancer, we previously showed that MIF knockout mice display decreased angiogenesis and invasion compared with wild-type. This study examines the role of MIF in bladder cancer via use of oral inhibitors of MIF. In vitro, high-grade bladder cancer cells were treated with recombinant human MIF +/- (rhMIF+/-) inhibitor. Measurements included cell counts, proliferation by (3)H-thymidine incorporation (TdR), extracellular signal-regulated kinase (ERK) phosphorylation by western blot analysis, messenger RNA (mRNA) expression by quantitative PCR and protein secretion by enzyme-linked immunosorbent assay. Treatment with rhMIF increased ERK phosphorylation, cell counts, TdR and mRNA expression and protein secretion of vascular endothelial growth factor, which were blocked by specific inhibitors of ERK and MIF. In vivo, 3-month-old male C57Bl/6 mice were given BBN for 22 and 16 weeks in study 1 and study 2, respectively. Mice (n = 8-10 per group) were gavaged with vehicle or doses of MIF inhibitors daily from weeks 16-22 in both studies. Average bladder weights, reflecting tumor mass, tumor stage/burden, mitotic rate and proliferation indices, and microvessel densities were reduced in inhibitor groups versus controls. In summary, MIF promotes bladder cancer via increasing cell proliferation and angiogenesis and oral inhibitors of MIF may prove useful in treatment of this disease.
authors.affiliation: Division of Urology.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Choudhary
authors.forename: Poornima
authors.initials: P
authors.lastname: Hegde
authors.forename: James R
authors.initials: JR
authors.lastname: Pruitt
authors.forename: Thais M
authors.initials: TM
authors.lastname: Sielecki
authors.forename: Dharamainder
authors.initials: D
authors.lastname: Choudhary
authors.forename: Kristen
authors.initials: K
authors.lastname: Scarpato
authors.forename: David J
authors.initials: DJ
authors.lastname: Degraff
authors.forename: Carol C
authors.initials: CC
authors.lastname: Pilbeam
authors.forename: John A
authors.initials: JA
authors.lastname: Taylor
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D056945:Hep G2 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt